The aim of the study was to determine the efficacy and toxicity of alternate week concurrent 5-fluorouracil, hydroxyurea, and cisplatin with radiotherapy for locally advanced pancreatic adenocarcinoma. Patients received 5-fluorouracil, hydroxyurea and cisplatin with radiotherapy on an alternate week basis. Chemoradiotherapy was given day 1-5, and no therapy given day 6-14 for each 14 day cycle. Chemotherapy doses were as follows: hydroxyurea 1 mg every 12 h starting day 0, 5-fluorouracil 800 mg/m(2)/day for 5 days starting day 1, and cisplatin 20 mg/m(2) daily for 5 days every other cycle. A radiation dose of 6000 cGy was prescribed. Acute toxicities were monitored and therapy modified for hematologic toxicity. Nine patients enrolled, however eight were evaluable; one patient expired prior to therapy. The median radiation dose delivered was 5540 cGy. Sixty-three percent required a chemotherapy dose reduction. Fifty percent achieved local control by radiographic imaging after completion of therapy. Median survival was 12 months. Acute toxicity included: 38% grade 2-3 nausea, 37% grade 2-3 vomiting, 63% grade 2-3 mucositis, 63% grade 2-3 neutropenia, and 88% grade 3-4 thrombocytopenia. Other sequelae included hand-foot syndrome, deep venous thrombosis, hearing loss, seizures, and anorexia. Patients achieved the same median survival as compared to other reported studies of radiation therapy with single agent 5-fluorouracil. We do not recommend this protocol due to the significant toxicity. Future studies to incorporate conformal radiation therapy with more active, less toxic chemotherapeutic agents should be investigated.